It is recognized that the use of certain therapeutic compounds, including anticancer, antibacterial, antiviral and antifungal compounds, is limited by inherent, toxic side effects, which at times may be irreversible and severe. The delivery of such compounds directly to their target sites of action is thus desirable, in order to avoid the toxic effects of systemic administration, which often counter the therapeutic effects sought to be achieved.
The use of certain therapeutic compounds is further limited, in many instances, because the compound may be degraded by natural metabolic processes, before it can reach its target site of action. As a result, much higher doses must be given to assure that an adequate amount of the therapeutic compound is available at the target site of action to elicit the desired response. Administration of these higher does may also result in toxic side effects, in addition to the inherent toxic effects already mentioned.
Methods to deliver such compounds to their target sites in a relatively undegraded form and in smaller amounts are, therefore, highly desirable. Rapid transport of therapeutic compounds directly to target sites avoids undue degradation and the systemic toxic effects associated with the use of these compounds, primarily because the dosage necessary to obtain the therapeutic effect can be reduced, thus reducing the effective amount of the compound in the systemic circulation.
It is further recognized that the use of certain therapeutic compounds is limited, because many of these compounds are not available in orally administerable forms, or are poorly absorbed orally. Thus, the only recourse is either to administer the compound parenterally, which may require hospitalization or expensive, outpatient intramuscular or intravenous therapy, or to treat a patient with a less desirable orally administerable compound. Neither of the foregoing options is optimal.
It is known in the art that oxo thia azabicyclo compounds, particularly .beta.-lactam compounds, possess certain superior pharmacokinetic properties which permit rapid and complete passage through host barriers, such as the G.I. tract, intestines, and other mucous membrane barriers; tissue barriers, such as the blood vessels, lymph nodes and others; cellular membrane barriers and intracellular barriers, such as the endoplasmic reticulum, mitochondria, nuclear membranes, and the nucleus itself. Likewise, the pharmacokinetic properties of such compounds also allow rapid and complete passage through the external and internal barriers of pathogen cells, including microorganisms and cancer cells.
Second, it is known that .beta.-lactam compounds are chemically reactive, because of the ring strain inherent in the .beta.-lactam ring. (Kirk-Othmer, Chem Tech. Encyclopedia, p. 881 (1984)). The geometry of the .beta.-lactam ring, with its accompanying increased ring strain, accounts for the greater reactivity of .beta.-lactam antibiotics. Ring-opening reactions take place under the influence of chemical reagents.
For example, the .beta.-lactam ring readily opens on reaction with various nucleophiles. After ring opening, .beta.-lactam compounds may undergo molecular rearrangement to form new compounds. Synthesis of various heterocyclic compounds, derived from strategically substituted .beta.-lactam compounds, via .beta.-lactam ring opening and intramolecular rearrangement, have been described in the literature. Manhas, M. S., Amin, S. G., and Bose, A. K., Heterocycles (1976), 5, 669. Manhas et al. describes the formation of compositions, such as carbostyril, coumarin, diazepin, thiazepin, etc., formed entirely by opening the .beta.-lactam ring, followed by intramolecular rearrangement of the .beta.-lactam compound itself. None of these compositions is used medically. Manhas et al. does not describe or disclose the preparation of useful pharmaceutical compositions by the use of .beta.-lactam ring opening and intramolecular rearrangement, followed by reclosing of the ring. Manhas et al. accomplishes intentional .beta.-lactam ring opening through vigorous chemical reactions, resulting in the complete breakdown of the fused .beta.-lactam ring.
Further, Manhas et al. does not describe or disclose a process for combining .beta.-lactam compounds with other biologically active parent compounds to form new compositions, which are equal in activity to the parent compound, but less toxic due to the lower amount of the parent compound contained in, and the improved pharmacodynamics of, the new composition. The compositions taught by Manhas et al. are formed entirely by .beta.-lactam ring-opening and intramolecuar rearrangement of the .beta.-lactam compound itself. No other compounds are added to, or contemplated for, the process described by Manhas et al.
It has been shown that the use of milder conditions may accomplish opening of the .beta.-lactam ring, followed by subsequent reclosing of the ring, without a complete breakdown of the .beta.-lactam ring structure. In addition, prior studies have shown that under certain conditions, wherein the .beta.-lactam ring is opened and reclosed, .beta.-lactam compounds, such as penicillin, may polymerize to form low molecular weight peptides. (Grant, Clark & Alburn, J.Am.Chem.Soc. 84, 876 (1962)). These studies were conducted in water, with the hydroxyl (--OH) group acting as the nucleophile. The resultant peptides were composed entirely of .beta.-lactam units and were biologically inactive.
Various sites on the .beta.-lactam penicillin molecule, where ring opening may take place, have been reported in the art. (Stoodley, R. J. et al., Tetrahedron Letters, 1205 (1966); Kitchin, J. & Stoodley, R. J., J.Chem Soc., 2460 (1973). For example, attack by nucleophiles and electrophiles on the carbonyl group of the .beta.-lactam ring results in ring opening. (Clarke, H. T., et al., Chemistry of Penicillin, Princeton University Press, Princeton, N.J. (1949)). Specifically, hydroxyl (--OH) groups, acting as nucleophiles, can attack the .beta.-lactam compound at the carbonyl site, resulting in the opening of the .beta.-lactam ring. (Wilson, Gisvold, Doerge, Textbook Org. Med. Pharm. Chem., 7th ed., pp. 276-77). Ring opening and intramolecular rearrangement, facilitated by nucleophilic attack, have also been reported by Morin, et al., J.Chem.Soc. 21, 1401 (1969).
Finally, it is known that compounds containing terminal amino (NH.sub.2) groups are capable of reacting and forming ionic and covalent bonds with themselves and with other molecules to form polymers known as polypeptides. These terminal amino groups will combine with other compounds at available receptor sites. The reaction consists of nucleophilic attack on a receptor site of another compound by the primary amino group of the terminal-amino-group-containing compound, with the resultant formation of polyamides of various chain lengths.
Compounds containing terminal amino groups are well known compounds in the art. Among the biologically active therapeutic compounds containing such groups are certain anticancer, antiviral, antifungal, antibacterial, antiparasitic, antiparkinsonian, neuromuscular, neuroleptic, antiarthritic, cardiovascular, pulmonic, renogenic, hepatogenic, lymphogenic, and hormonal compounds, including certain steroidal and endocrine compounds, and insulin. The therapeutic use of these known compounds often requires the administration of high doses to achieve the intended therapeutic effect, often resulting in serious toxic side effects or complications. In many instances, these compounds cannot be administered orally, or are poorly absorbed orally.
Oxo thia azabicyclo compounds, including the lactams and .beta.-lactam compounds, are also well-known in the art. Among the naturally occurring .beta.-lactam compounds are antibiotics such as penicillins, cepalosporins, cephamycins, cephems, penams, monobactams, and nocardicins, to name a few. There are, of course, countless other lactams and .beta.-lactam compounds, which are believed to be useful in the present invention. The essential feature is the presence of the .beta.-lactam ring, which is amenable to nucleophilic attack, resulting in opening of the .beta.-lactam ring, followed by intramolecular rearrangement, and ring reclosing.
It is one object of the present invention to produce useful, pharmaceutical compositions, prepared by combining biologically active parent compounds with .beta.-lactam compounds in a manner heretofore unknown, which are highly efficacious at lower doses and less toxic than the parent compounds when used alone.
It is a further object of this invention to provide a process for combining a biologically active parent compound with a .beta.-lactam compound.
It is yet a further object of the invention to produce useful, pharmaceutical compositions which are capable of rapidly delivering parent compounds relatively undegraded to their target sites.
Still another object of the invention is to provide orally administerable pharmaceutical compositions, which have the same therapeutic activity at lower doses and less toxicity than the parent compound from which they were derived.
Such objects and further advantages of the invention will be apparent from the detailed description which follows.